Uric acid is a metabolite of purine in vivo. Due to the lack of uricase, which degrades uric acid in the human body, uric acid is mainly excreted from the body through the kidney and intestine, wherein the kidney is the major route of uric acid excretion. Transportation of uric acid in the kidney directly regulates the level of serum uric acid. Decreased excretion or increased production of uric acid can lead to hyperuricemia, 90% of which is caused by the decrease of uric acid excretion. Recently, the prevalence of hyperuricemia and gout has increased significantly with the improvement of people's living standard. Hyperuricemia and primary gout show a significant positive correlation with obesity, hyperlipidemia, hypertension, diabetes and atherosclerosis etc. Therefore, hyperuricemia and gout are metabolic diseases seriously harmful to human health, similar to diabetes.
Hyperuricemia refers to a body condition with the concentration of uric acid in the blood beyond the normal range (37° C., serum uric acid content is over 416 μmol/PL (70 mg/PL) in male; over 357 μmol/PL (60 mg/PL) in female). In 2009, hyperuricemia prevalence was 10.0% in the Shanghai area, with 11.1% for males, and 9.4% for females; hyperuricemia prevalence in Beijing was 17.86% among 1120 subjects, with 25.74% for males and 10.52% for females; the prevalence of the Guangzhou area ranked first in the country with 27.9% for males and 12.4% for females, and the total prevalence rate was up to 21.81%.
Gout is a heterogeneous, metabolic disease caused by long-term purine metabolic disorder and/or decreased uric acid excretion. Gout can be divided into primary and secondary types, its clinical features are hyperuricemia, recurrent acute arthritis, and are generally associated with cardiovascular and cerebrovascular diseases, thereby threatening human life. High-risk populations include men and menopausal women; and the peak incidence is 40-50 years old. The prerequisite cause of gout is hyperuricemia, when uric acid content in serum extends beyond the normal range, and urate deposition in tissues can also cause gout histological changes. 5%-12% of hyperuricemia patients eventually developed gout only when they appeared to have the symptoms of urate crystal deposition, arthritis, kidney disease, kidney stone etc.
Physiological and pharmacological studies found a kidney urate transport classic mode: glomerular filtration, renal tubular reabsorption, renal tubular secretion and reabsorption after secretion. Any factor that impacts the aforesaid four processes will impact renal excretion of uric acid. More than 98% of uric acid filtrated by glomerulus can be reabsorpted and then secreted by proximal renal tubule, which is the most important factor that impacts uric acid excretion. Proximal convoluted tubule (also known as proximal tubule curved portion) SI segment is a reabsorption place, 98% to 100% of filtrated uric acid enters into the epithelial cells here via the urate transporter 1 (URAT1) in the brush border membrane of tubular epithelial cells.
URAT1 is also called OAT4L (organic anion transporter 4-like) or urate anion exchanger 1. Human URAT1 (hURAT1), encoded by the SLC22A12 gene (containing 10 exons and 9 introns) on chromosome 11 q 13, has 42% homology with OAT4. Human URAT1 is a complete transmembrane protein of 555 amino acid residues, consisting of 12 transmembrane domains, a —NH2 terminal domain and a —COOH terminal domain located inside the cell. Enomoto et al. (Nature. 2002; 417(6887): 447-52) found that hURAT1 had a function of transporting urate, which was time-dependent and saturated. Studies found that SLC22A12 gene carried in renal hypouricemia patients was mutated, thereby losing the ability of encoding URAT1, which suggested that URAT1 was important for uric acid reabsorption in the kidney. Specific mutations of the URAT1 gene sequence of Japanese carrying SLC22A12 heterozygous decreased the serum uric acid concentration and gout incidence. Iwai et al. (Kidney Int. 2004; 66(3): 935-44) studied SLC22A12 gene polymorphisms in Japanese population, and found that particular polymorphisms of the gene were related to hypouricemia, and expression in vitro demonstrated that some mutations can lead to loss of the uric-acid-transport function of URAT1. Taniguchi et al. (Arthritis Rheum. 2005; 52(8): 2576-2577) found that the G774A mutation of SCL22A12 inhibited gout occurrence, and the serum uric acid level in patients with heterozygous G774A mutation was significantly lower than in healthy people. Graessler et al. (Arthritis Rheum. 2006; 54(1): 292-300) reported that an N-terminal gene polymorphism found in Germany's Caucasian population was related to a decrease of renal uric acid excretion. Guan et al. (Scand J Rheumatol. 2009; 38(4): 276-81) studied polymorphisms of the sr893006 gene sequence of SLC22A12 in 124 primary gout patients and 168 healthy Chinese male subjects, suggesting that the polymorphism of this gene sequence may be a genetic risk factor for Chinese male patients with hyperuricemia. URAT1 will be a new target for the development of a drug for treating gout and hyperuricemia.
Currently, there are many compounds for treating hyperuricemia and gout in clinical trials and the marketing stage, in which URAT1 specific inhibitors in clinical trials are only lesinurad (phase III) and RDEA-3170 (Phase I) from Ardea Biosciences. Patent applications disclosing URAT1 inhibitors include WO2006057460, WO2008153129, WO2010044403, WO2011046800 and WO2011159839, etc.
In order to achieve better treatment, and to better meet the market demands, we hope to develop a new generation of URAT1 inhibitors with high efficiency and low toxicity. The present disclosure provides new structural URAT1 inhibitors, and it is found that compounds having such structures have good activity, and exhibit excellent decrease of serum uric acid concentration, and treatment effect for hyperuricemia and gout.